One‐Pot Functionalization of 8‐Aminoquinolines through the Acylation and Regioselective C5‐H Halogenation under Transition‐Metal‐Free Conditions

Abstract

A mild and efficient functionalization of 8‐aminoquinolines has been demonstrated through the acylation and regioselective C5‐H halogenation in one pot under transition metal free conditions. This method enables the acyl halides acting as the donors of both acyl and halide atoms. Moremover, different type of acyl halides could be employed in this reaction and proceeded smoothly to afford the corresponding halogenated products in moderate to good yields. The protocol is operationally simple, facile, and might have potential application in synthesis of 5‐halogenated quinoline scaffolds.

Recent Update on Transition Metal‐Free C(sp2)−H Bond Halogenation in (Hetero) Arenes

“…Acyl halides (130)can also act as effective halogenating agents. Liet al in 2019 developed [90] an one-pot transition-metal free C(5)À H halogenation of 8-aminoquinolines (129)along with acylation of the free amine present in 8-aminoquinoline (Scheme 80). In this protocol, the acyl halides thus played a dual role by regioselectively inserting halogen atom and providing acyl protection to the free amine.…”

“…Oxone [82] /NaX (X=Cl/Br) N-halosaccarine [87] NaXO 2 [97] X=Cl/Br Ar 2 S 2 [44] /DIH I 2 / PhI(OAc) 2 [45] MOP,HBr,O 2 ,Light [23] LiX/K 2 S 2 O 8 [83] (X=Cl/Br/I) NXS(X=Cl/Br/I) HFIP [51] PhI(OAc) 2 [81] RX (X=Cl/Br) or HX (X=Cl,Br, OMs,OTs,OTf) DBH [39] HBr,Selectfluor [34] NaX/K 2 S 2 O 8 [84] (X=Cl/Br/I) Trihalo (Cl/Br/I) Isocyanuric acid [88] Oxone [90] /Acyl halide Visible-light, TBCA [40] NXS/H 2 O [86] Selectfluor [57] KHCO 3 Selectfluor [58] AcOH ArSO 2 X [75] (X=Cl,Br)…”

Copper-promoted C5-selective bromination of 8-aminoquinoline amides with alkyl bromides

“…However, reports on the bromination of C5–H of 8-aminoquinolines employing acyl bromides, alkyl bromides, and aryl bromides as bromination reagents are limited. Wan and Li, respectively, demonstrated a few examples of a one-pot N -acylation and C5–H bromination of 8‑aminoquinolines using acyl bromines acting as both acyl and halide donors [ 25 – 26 ]. The groups of Lei and Fang independently realized the selective C5-bromination of 8-aminoquinoline amides using carbon tetrabromide and dibromomethane under photo- and electrocatalysis conditions [ 27 – 28 ].…”